Abstract

Background: The indolent (follicular, marginal zone and mantle cell) lymphomas tend to recur with decreasing intervals of remission after standard chemotherapy. New modalities of treatment are necessary. Vorinostat (SAHA), an orally administered hydroxamic acid histone deacetylase inhibitor with activity against class I and II deactylases with preclinical and clinical activity against various forms of lymphoma, is being studied in patients with relapsed or refractory indolent lymphoma. We report the results at the first interim analysis, after accrual of the first 17 evaluable patients according to the two-stage trial design.

Methods: Patients with relapsed or refractory follicular, marginal zone, or mantle cell lymphoma are eligible. Vorinostat is dosed at 200 mg po twice daily for 14 consecutive days on a 21 day cycle. CT scanning is performed after every three cycles, as is marrow biopsy for those with marrow involvement at time of entry into study. Patients may have received up to four prior chemotherapy regimens including Zevalin or Bexxar; previous transplant is allowed.

Results: 17 eligible patients (8 female, 9 male) were accrued prior to interim analysis (1 ineligible patient due to wrong histology is excluded from the analysis). The median age at diagnosis was 61 (34–78) years. All patients had progressed or failed to respond to chemotherapy and/or rituximab. Five patients were taken off study due to progression, two came off study due to toxicities (one for fatigue and diarrhea after 10 cycles and the other for diarrhea and dizziness after 2 cycles). One patient stopped therapy due to intercurrent illness, one came off for alternate therapy, 1 completed the treatment per protocol with a CR, and 7 patients remain on treatment. One patient had grade 4 ANC and thrombocytopenia, and one patient had grade 4 thrombocytopenia. Both patients were able to get subsequent cycles. Grade 3 toxicities attributable to study drug were thrombocytopenia, neutropenia, anemia, and fatigue. By the current Cheson criteria, there were 4 patients who achieved complete remission (CR), and 2 patients who achieved partial remission (PR). The two patients with PR as best response subsequently progressed (one at 189 days, one after 462 days). Four other patients are on therapy with stable disease, one patient with stable disease now for over 420 days.

Conclusions: The histone deacetylase inhibitor vorinostat shows promising activity against follicular and marginal zone lymphoma, refractory to chemotherapy and rituximab. The target response for stage 1 (4/17) was met and stage 2 is open for accrual.

Author notes

Disclosure:Membership Information: Dr. Kirschbaum: Speaker’s Bureau for Merck. Off Label Use: Use of Vorinostat in indolent lymphoma, not currently an FDA approved indication.